The mast cell precursor in human peripheral blood is CD34+/FcepsilonRI-. The number of mast cells arising per CD34+ cell in culture is greater when the CD34+ cells are obtained from patients with mastocytosis with a hematologic disorder compared to normal subjects. This observation led us to search for mutations in the receptor for SCF, c-kit, which would result in enhanced cell proliferaton. Using SSCP analysis of PCR products, and genomic DNA analysis, we identified a mutation in c-kit which has been reported in murine and human mast cell lines to result in increased mast cell proliferation. This mutation was associated with mastocytosis in which a hematologic disorder was also present and which exhibited predominantly myelodysplastic features. This mutation was not identified in 67 normal subjects, or in patients with agressive mastocytosis, and was usually absent in patients with indolent mastocytosis. Interferon alpha-2b was administered to 3 patients with progressive forms of mastocytosis for periods in excess of one year. All patients demonstrated continued progression of disease in spite of interferon alpha-2b adminis-tration. Mast cell tryptase in the serum of patients with mastocytosis differs from the tryptase released during anaphylaxis. This difference is recognized by specific monoclonal antibodies and may provide an improved means to follow disease progression and response to theapy. The tryptase found in the sera of mastocytosis is, however, identical to the tryptase found in the sera of patients not experiencing mast cell degranulation, i.e. the "resting tryptase".